Ultram ER

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Ultram ER

SIDE EFFECTS

ULTRAM ER (tramadol hcl extended-release) was administered to a total of 3108 patients during studies conducted
in the U.S. These included four double-blind studies in patients with osteoarthritis
and/or chronic low back pain and one open-label study in patients with chronic
non-malignant pain. A total of 901 patients were 65 years or older. The frequency
of adverse events generally increased with doses from 100 mg to 400 mg in the
two pooled, twelve-week, randomized, double-blind, placebo-controlled studies
in patients with chronic non-malignant pain (see Table 2).

Serotonergic Drugs: There have been postmarketing reports of serotonin syndrome
with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers.
Caution is advised when ULTRAM ER (tramadol hcl extended-release) is coadministered with other drugs that may
affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans,
linezolid (an antibiotic which is a reversible non-selective MAOI), lithium,
or St. John's Wort. If concomitant treatment of ULTRAM ER (tramadol hcl extended-release) with a drug affecting
the serotonergic neurotransmitter system is clinically warranted, careful observation
of the patient is advised, particularly during treatment initiation and dose
increases (see WARNINGS, Serotonin Syndrome).

Triptans: Based on the mechanism of action of tramadol and the potential for
serotonin syndrome, caution is advised when ULTRAM ER (tramadol hcl extended-release) is coadministered with
a triptan. If concomitant treatment of ULTRAM ER (tramadol hcl extended-release) with a triptan is clinically
warranted, careful observation of the patient is advised, particularly during
treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Use With Carbamazepine

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly
reduced analgesic effect of tramadol. Because carbamazepine increases tramadol
metabolism and because of the seizure risk associated with tramadol, concomitant
administration of ULTRAM ER (tramadol hcl extended-release) and carbamazepine is not recommended.

Use With Quinidine

Coadministration of quinidine with ULTRAM ER (tramadol hcl extended-release) resulted in a 50-60% increase
in tramadol exposure and a 50-60% decrease in M1 exposure (see CLINICAL PHARMACOLOGY,
Drug Interactions). The clinical consequences of these findings are unknown.

Use With Digoxin and Warfarin

Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin
times.

Potential for Other Drugs to Affect Tramadol

In vitro drug interaction studies in human liver microsomes indicate that concomitant
administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and
amitriptyline could result in some inhibition of the metabolism of tramadol.

Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin,
or inducers, such as rifampin and St. John's Wort, with ULTRAM ER (tramadol hcl extended-release) may affect
the metabolism of tramadol leading to altered tramadol exposure.

Potential for Tramadol to Affect Other Drugs

In vitro drug interaction studies in human liver microsomes indicate that tramadol
has no effect on quinidine metabolism. In vitro studies indicate that tramadol
is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered
concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug
metabolism pathways measured in animals.

Drug Abuse And Addiction

ULTRAM ER (tramadol hcl extended-release) is a mu-agonist opioid. Tramadol, like other opioids used in analgesia,
can be abused and is subject to criminal diversion.

Drug addiction is characterized by compulsive use, use for non-medical purposes,
and continued use despite harm or risk of harm. Drug addiction is a treatable
disease, utilizing a multi-disciplinary approach, but relapse is common.

“Drug-seeking” behavior is very common in addicts and drug abusers.
Drug-seeking tactics include emergency calls or visits near the end of office
hours, refusal to undergo appropriate examination, testing or referral, repeated
“loss” of prescriptions, tampering with prescriptions and reluctance
to provide prior medical records or contact information for other treating physician(s).
“Doctor shopping” to obtain additional prescriptions is common among
drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and
tolerance. Physicians should be aware that addiction may not be accompanied
by concurrent tolerance and symptoms of physical dependence in all addicts.
In addition, abuse of opioids can occur in the absence of true addiction and
is characterized by misuse for non-medical purposes, often in combination with
other psychoactive substances. ULTRAM ER (tramadol hcl extended-release) , like other opioids, may be diverted
for non-medical use. Careful record-keeping of prescribing information, including
quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation
of therapy, and proper dispensing and storage are appropriate measures that
help to limit abuse of opioid drugs.

ULTRAM ER (tramadol hcl extended-release) is intended for oral use only. The crushed tablet poses a hazard
of overdose and death. This risk is increased with concurrent abuse of alcohol
and other substances. With parenteral abuse, the tablet excipients can be expected
to result in local tissue necrosis, infection, pulmonary granulomas, and increased
risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly
associated with transmission of infectious diseases such as hepatitis and HIV.

Risk of Overdosage

Serious potential consequences of overdosage with ULTRAM ER (tramadol hcl extended-release) are central nervous
system depression, respiratory depression and death. In treating an overdose,
primary attention should be given to maintaining adequate ventilation along
with general supportive treatment (see OVERDOSAGE).